Formulation and evaluation of hydrogel-forming microarray patches for transdermal primaquine and chloroquine delivery in malaria therapy

Malaria remains a pressing global health challenge. The standard treatment for malaria involves a combination of chloroquine (CQ), which targets blood-stage parasites, and primaquine (PQ), which eliminates hepatic hypnozoites to prevent relapses. However, these drugs present limitations, including poor adherence due to frequent oral dosing and gastrointestinal side effects. To address these challenges, this study successfully developed, optimised, and characterised lyophilised reservoirs loaded with PQ and CQ, which were incorporated into hydrogel-forming microarray patches (MAPs) for improved malaria treatment. Using a Design of Experiments (DoE) approach, the optimised lyophilised reservoirs dissolved rapidly, within 7 s for CQ and 16 s for PQ. In vitro permeation studies using dermatomed neonatal porcine skin demonstrated efficient drug delivery of approximately 40 mg (70 % delivery efficiency) of each drug over 24 h. Pharmacokinetic analysis in rats showed that MAP administration significantly increased C max values from 0.23 ng/mL to 2.23 ng/mL for CQ, and from 13.84 ng/mL to 59.22 ng/mL for PQ compared to oral delivery. Moreover, the area under the curve (AUC 0-72h ) for the MAP group was 35-fold higher for CQ and 2-fold higher for PQ compared to oral administration. Efficacy studies in a murine malaria model demonstrated that MAP-delivered PQ and CQ reduced parasitaemia by 99.8 % in treated animals. These findings highlight the potential of MAP technology as a minimally-invasive, sustained drug delivery platform for malaria treatment, potentially offering improved patient adherence, reduced hepatoxicity, and enhanced therapeutic outcomes. • Developed hydrogel-forming MAPs with lyophilised primaquine and chloroquine reservoirs for malaria therapy. • Optimised reservoirs rapidly dissolved (7 s for chloroquine, 16 s for primaquine) using Design of Experiments approach. • Achieved ~70 % transdermal delivery efficiency of primaquine and chloroquine over 24 h in vitro . • MAPs significantly enhanced systemic exposure of primaquine and chloroquine in rat pharmacokinetics. • MAPs reduced parasitaemia by 99.8 % in a murine Plasmodium berghei malaria model.